1. Field of the Invention
The present invention relates to reconstituted pulmonary surfactants which are suitable for the prophylaxis and/or treatment of respiratory distress syndrome (RDS) and other respiratory disorders. The present invention also relates to methods for the prophylaxis and/or treatment of respiratory distress syndrome (RDS) and other respiratory disorders by administering such a pulmonary surfactant.
2. Discussion of the Background
The human lung is composed of a large number of small air sacs, called alveoli, in which gases are exchanged between the blood and the air spaces of the lungs. In healthy individuals, this exchange is mediated by the presence of a protein-containing surfactant complex that prevents the lungs from collapsing at the end of expiration.
Lung surfactant complex is composed primarily of lipid and contains minor amounts of various proteins. An absence of adequate levels of this complex results in malfunction of the lung. This syndrome is called Respiratory Distress Syndrome (RDS) and it commonly affects preterm infants.
Said syndrome is effectively treated with commercially available modified natural surfactant preparations extracted from animal lungs, such as the gold standard preparation known as Curosurf®. The main constituents of these surfactant preparations are phospholipids and surfactant hydrophobic proteins B and C (SP-B and SP-C).
Due to the drawbacks of the surfactant preparations from animal tissues, such as the complication of the production process, and possible viral contamination and/or induction of immune reactions, synthetic surfactants have been made available in the art.
Said synthetic surfactants can be simply mixtures of synthetic compounds, primarily phospholipids and other lipids and are known as “artificial” surfactants; although they have been used in clinical practice for many years, their efficacy is not comparable to that of modified natural surfactant.
Artificial surfactants also containing surfactant proteins/peptides are also currently under development. They are termed either “reconstituted” surfactants or “bio-mimetic surfactants”.
However, according to the available literature, none of the reconstituted surfactants developed so far has shown an efficacy in terms of lung compliance comparable to that of the surfactants extracted from animals. Moreover they give rise to poor lung gas volumes and grade of alveolar patency at the end of expiration, and a ventilation is required with a positive end expiratory pressure (PEEP) in order to achieve an in vivo activity comparable to that achieved with modified natural surfactants (see, Johansson J et al, J Appl Physiol, 2003, 95, 2055-2063; Davis A J et al, Am J Respir Crit Care Med, 1998; 157, 553-559).
A possible explanation is that the reconstituted surfactants under development do not reproduce the complete proteinaceous profile of the modified natural surfactants as they comprise only one proteinaceous (peptide) component.
On the other hand, besides good efficacy, surfactant compositions should also exhibit a low viscosity to allow the preparation of a concentrated suspension in an aqueous medium. The possibility of preparing a concentrated suspension in a small volume is indeed a feature of particular importance for their administration to very low-weight newborns.
The peptide:phospholipid system is a rather complex mixture whose properties greatly depend on the composition of the phospholipid mixture as well as on the specific phospholipids/peptide combination. The presence of a further peptide would affect the rheological properties of the composition making the system even more complicated.
In the prior art, reconstituted surfactants comprising both SP-B and SP-C analogues resembling human surfactant proteins have been disclosed, for example in WO0076535, WO2008011559 and WO2008044109. However, none of the compositions disclosed therein have been shown to possess optimal properties in terms of lung compliance as well as rheological properties, in particular viscosity.
Accordingly, there is still a need for reconstituted surfactant preparations having a comparable efficacy to that of the surfactants extracted from animal lungs as well as optimal rheological properties allowing their easy delivery and distribution into the broncho-alveolar part of the lungs upon administration.